SELECTIVE RETINOIDS FOR BREAST CANCER THERAPY

视黄醇反应的多样性是在多个水平上调节的。 三种维甲酸和维甲酸X在其信号通路中的作用 受体(RAR和RXR)亚型由它们的 细胞分布模式的变异及其直接和间接 调节基因转录的机制。正因为如此 多样性，潜力高，更有效，毒性更小 选择性维甲酸可用于乳房的治疗 癌症，每12名女性中就有一人罹患癌症。p53基因突变 肿瘤抑制基因与对生长抑制的抗性 维甲酸的作用与乳腺肿瘤的增加有关 恶性肿瘤和转移。然而，我们已经确定了唯一的 维甲酸的一类，当与其他物质结合使用时 维甲酸或干扰素或作为RAR/RXR泛激动剂发挥作用 或凋亡诱导剂抑制生长和克隆性增殖 正常的维甲酸耐药的乳腺癌细胞，无论它们的 P53状态。在该计划项目中(选择性维甲酸 用于乳腺癌治疗的选择性维甲酸)，我们建议一种 涉及四个研究项目和一个项目的多学科努力 核心成分，用于研究其分子机制 维甲酸对乳腺癌细胞有抑制作用。这个 由此产生的知识将使我们随后能够识别 治疗这种疾病的最佳候选药物。类维甲酸 维甲酸项目的设计和综合工作 合成将为研究作用机制提供必要的探索 生物评价的研究和候选人。项目分子 维甲酸的作用机制将(1)研究RARbeta如何 与BetaRARE相互作用或在乳腺癌中丢失和(2) 评估靶标诱导或抑制基因的能力 抄写。维甲酸-受体相互作用项目将(1)研究 视黄醇诱导的RARs和RXRs AS的构象变化 单独或与维甲酸反应元件结合的异二聚体；(2)使用 一种体外转录系统来评估细胞外信号的调节 RARbeta反应，以及(3)维甲酸受体的特征 6-[3-(1-金刚烷基)]-2-萘甲酸(AHPN) 不依赖维甲酸受体诱导细胞凋亡。项目 乳腺癌中的细胞凋亡将(1)探讨其机制 AHPN通过示踪AHPN在乳腺中的凋亡活性而发挥作用 癌细胞株及AHP受体的分离；(2)评价 AHPN类似物对乳腺癌细胞的抑制作用 ；及。(3)进行乳癌移植研究。 最佳的维甲酸/AHPN类似物。生物鉴定核心将进行 (1)维甲酸受体结合研究，(2)血管生成试验，以及 (3)药理/毒理/代谢评估，以协助 选择生物评价的目标或用作机械学的项目 运用决策网络方法进行了探讨。

The diversity of the retinoid response is mediated at multiple levels in their signaling pathways by the three retinoic acid and retinoid X receptor (RAR and RXR) subtypes that is compounded by their variation in cell distribution patterns and their direct and indirect mechanisms for modulating gene transcription. Because of this diversity, the potential is high that more effective, less toxic selective retinoids can be identified for the treatment of breast cancer, which will afflict one woman in 12. Mutations in the p53 tumor suppressor genes and resistance to the growth inhibitory effects of retinoids are associated with increased breast tumor malignancy and metastasis. However, we have identified unique classes of retinoids that when used in combination with other retinoids or interferon or by functioning as RAR/RXR panagonists or inducers of apoptosis inhibit the growth and clonal proliferation of normally retinoid-resistant breast cancer cells, regardless of their p53 status. In this Program Project (Selective Retinoids for Selective Retinoids for Breast Cancer Treatment), we propose a multidiscriplinary effort involving four Research Projects and one Core Component to investigate the molecular mechanisms by which retinoids exert their inhibitory effects on breast cancer cells. The resulting knowledge will subsequently allow us to identify the optimum candidates for treatment of this disease. The retinoid design and synthesis efforts of Project Retinoid Design and Synthesis will provide essential probes for mechanism of action studies and candidates for bioevaluation. Project Molecular Mechanism of Retinoid Action will (1) investigate how RARbeta interacts with the betaRARE or is lost in breast cancer and (2) evaluate the targets for their abilities to induce or repress gene transcription. Project Retinoid-Receptor Interaction will (1) study retinoid-induced conformational changes in the RARs and RXRs as heterodimers alone or bound to retinoid response elements; (2) use an in vitro transcription system to assess modulation of the RARbeta response, and (3) characterize the receptor for the retinoid 6-[3-(1-adamantyl)]-2-naphthalenecarboxylic acid (AHPN), which induces apoptosis independently of the retinoid receptors. Project Apoptosis in Breast Cancer will (1) investigate the mechanism of action of AHPN by tracing AHPN apoptotic activity in breast cancer cell lines and isolating the AHP receptor; (2) evaluate AHPN analogs for their inhibitory activity against breast cancer cell growth; and (3) conduct breast cancer xenograft studies on the optimum retinoids/AHPN analogs. The Bioassay Core will conduct (1) retinoid receptor binding studies, (2) an angiogenesis assay, and (3) pharmacologic/toxicological/metabolic assessment to assist the Projects in selecting targets for bioevaluation or use as mechanistic probes by the Decision Network method.